This invention relates to aryl-substituted thiophene 3-ols, its dihydro derivatives, 1-oxide and 1,1-dioxide analogs, as well as aryl substituted furans, alal having the general formula: ##STR1## wherein Z represents the number of double bonds and is 1 or 2; Y is S, SO, SO.sub.2 or O; R.sub.1 forms an alcohol derivative or ester, acetal, carbonate, carbamate, aralkyl or acetol group; and R.sub.2 is H, alkyl, or aryl.
The compounds of this invention are 5-lipoxygenase inhibitors and are useful in the treatment of inflammation and other leukotriene-mediated diseases.
Among various potent biological mediators derived from the oxygenation of arachidonic acid, compounds characterized as prostaglandins or leukotrienes have been linked to various diseases. Notably, the biosynthesis of prostaglandins has been identified as a cause of inflammation, arthritic conditions (e.g., rheumatoid arthritis, osteoarthritis and gout), psoriasis, inflammatory bowel disease, and pain. Furthermore, the formation of leukotrienes has been connected to immediate hypersensitivity reactions and proinflammatory effects. It has been established that arachidonic acid undergoes oxygenation via two major enzymatic pathways:
(1) The pathway catalyzed by the enzyme cyclooxygenase; and PA0 (2) The pathway catalyzed by the enzyme 5-lipoxygenase. PA0 5 membered ring and Z is 1 or 2; and PA0 Y is S, SO, SO.sub.2 or O; PA0 R.sub.1 is H, acyl, aroyl, carbonate, carbamoyl, alkoxyalkyl, or alkylthioalkyl; PA0 R.sub.2 is H, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, aralkyl, alkyl, alkoxy, haloalkyl, halo, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, amino, nitro, cyano, acyl, aroyl, acylalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, bridged methylene, alkylthioalkyl, alkylsulfinylalkyl, alkylsulf-onylalkyl, arylthio, arylsulfonyl, arylsulfonyl, or cycloalkyl; wherein at least one R.sub.2 group must be an aryl or heteroaryl. PA0 Ac.sub.2 O=acetic anhydride PA0 ag.=aqueous PA0 DBU=1,8-diazobicyclo [5.4.0] undec-5-ene PA0 DDQ=2,3-dichloro 5,6-dicyano-1,4-benzoguinone PA0 4-DMAP=4 dimethylaminopyridine PA0 Pyr=pyridine PA0 t-BuOK=potassium tert-butoxide PA0 THF=tetrahydrofuran PA0 R.sub.1 is PA0 R.sub.2 is PA0 R.sub.2 is aryl at the 2 position of thiophene or the 5-position thereof, or both;
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof play an important role in causing inflammation (B. Samuelson, Science, 220, 568 (1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982))
For example, acute systemic anaphylaxis and other immediate hypersensitivity reactions are accompanied by the release of several mediators, including three leukotrienes, LTC.sub.4, LTD.sub.4 and LTE.sub.4. These three leukotrienes have the properties of inducing bronchoconstriction and alteration in vascular permeability. A fourth leukotriene, LTB.sub.4, has potent effects on chemotoxis and adherence of leukocytes. All four of these leukotrienes are produced by action of the enzyme 5-lipoxygenase on arachidonic acid. See, e.g. D. R. Robinson et al., J. Exp. Med. 163, 1509 (1986).
Through recent research, 5-lipoxygenase inhibitors have also been linked to the treatment of eye inflammation and used as cytoprotective agents.
To be an effective and acceptable topical agent for treating eye inflammation, a drug must not only penetrate the ophthalmic tissues to reach the active sites within the eye, but it must also be devoid of those side effects including irritation, allergic reaction and the like, which are contra-indications to long term administration.
With respect to the cytoprotective activity, it has been known that (1) gastric cytoprotection does not involve inhibition of gastric acid secretion. For example, prostaglandin F2B does not inhibit gastric acid secretion, but it does induce gastric cytoprotection (S. Szabo et al., Experimentia, 38, 254, 1982); (2) lower effective dosages of cyto-protective agents are required than that of gastric acid inhibitors; and (3) the cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of gastrointestinal mucosa to strong irritants. For example, animal studies have shown that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline, etc.